Ethanol has important cardiovascular effects, including inhibition of the depressor baroreflex response. GABA is the main inhibitory neurotransmitter in the CNS, and hypothalamic GABAergic neurons exert powerful inhibition of the baroreflex at the level of the nucleus tractus solitarii (NTS). As the first step toward our long range goal to clarify the effects of ethanol on cardiovascular regulation, we examined the mechanism of the pressor response of the GABA-B agonist baclofen at the level of the NTS. In urethane-anesthetized rats, intra-NTS baclofen caused dose-dependent pressor effects and tachycardia and inhibited baroreflex bradycardia elicited by iv. phenylephrine. The effects of baclofen were inhibited by intra-NTS phaclofen and 2-OH-saclofen, as well as by the non-NMDA glutamate antagonist DNQX and by ic. pretreatment with pertussis toxin (PT). DNQX and PT, but not the NMDA antagonist MK-801, also inhibited baroreflex bradycardia. Intra-NTS glutamate caused hypotension and bradycardia, which were potentiated by baclofen, and not inhibited by either DNQX, MK-801 or PT. These findings indicate that the cardiovascular effects GABA-B receptor stimulation in the NTS are due, at least in part, to inhibition of the depressor baroreflex response. Inhibition of the release and/or action of an excitatory amino acid other than glutamate is the most likely mechanism. In a subsequent study we found that the GABA-A agonist, muscimol, also causes pressor effects and inhibits baroreflex bradycardia, when injected into the NTS. Iv. or intra-NTS ethanol also inhibited baroreflex bradycardia and potentiated the effects of muscimol. The baroreflex inhibitory action of ethanol was eliminated by depletion of GABA by 3-mercaptopropionate, and reduced by bicuculline or by RO-15-4513. These findings suggest that ethanol inhibits the baroreflex partly through potentiation of the effects of endogenous GABA on GABA-A receptors in the NTS.